Catecholamines:resuscitation or resurrection?UNSWJohn MyburghMBBCh PhD FCICM FAICDThe George Institute for Global HealthSt...
What is knowledge?
Hein: Cell Tissue Research 2006Neurohormonal vasoregulation
Neurohormonal vasoregulationSadowska : J Physiol Pharm 2006VPNoradrenalineAdrenalineCortisol
Mean arterialpressureCardiac outputRight atrialpressureMean systemic pressurePerfusion pressureUnstressedvolumeStressedvol...
Barcroft: Lancet 1949n=7Human studiesGoldenberg : Arch Int Med 1950
Steele: Curr Opin Crit Care 2000What the textbooks say …….
What is “best” evidence?
Synthetic catecholamines
OHCH2CH2NHCHCH2CH2OHCH3OH .HClCHOHCH2 NHCHOHOHCH3CH3OHCH2CH2NHCH2CH2CH2CH2CH2CH2NHCH2CH2OH.2HClIsoprenalineDobutamineDopex...
CostDose Cost(AUD)Adrenaline 6 mg 11Noradrenaline 6mg 20Dopamine 400mg 37Dobutamine 500mg 119Dopexamine 50mg 390Isoprenali...
Dobutamine and sepsisn Dose(µg/kg/min)Endpoint Mortality GradeHayes 1994 100 5-200 DO2, VO2 34 v 54* IIIYu 1993 67 5-20 DO...
Maximising DO2 : the evidenceAchieving “supranormal” DO2 andVO2 does not affect mortalityMay benefit preoperativelyRespond...
Catecholamines and septic shockn Drug Dose Endpoint GradeDuranteau 1999 12 Adr ± Nor MAP >80 pHi IIIJoly 1999 14 Dob 7.5 µ...
“Goal Directed Therapy”Rivers: NEJM 2001
Human trialsNo conclusive evidenceDescriptive, observational, underpoweredVariable dose ranges, selection criteriaVariable...
Evidence-based guidelinesDellinger: CCM 2004, 2008
“Inotropes”Dellinger: ICM 2008
Biologically plausible, but unrelated to the evidence presentedPublication biasIntervention biasRegional biasAdrenaline ge...
Noradrenaline + DobutamineAdrenalinepHiHoursAdrenaline “toxicity”?Splanchnic ischaemiaLevy: ICM 1997n=23Malaria n=13Severe...
What is “best” evidence?
Mullner: Cochrane Collaboration 2007
Systematic review: 2007Intervention n RR 95%CIADR v NOR 0 0 0NOR + DOB vs ADR 52 0.98 0.57 to 1.67NOR vs DOP 62 0.88 0.57 ...
What is “best” evidence?
Myburgh: ICM 2008Relative effectiveness blinded MC RCTn=280Primary outcome: Clinician-prescribed target MAP > 24 hours2004...
Myburgh: ICM 2008
Annane: Lancet 2007Blinded MC RCTn=330Primary outcome: D28 mortality1999-2004
No difference in secondary outcome measures:Haemodynamic endpointsDose of drug(s)Organ failure resolutionICU LOSEpinephrin...
De Backer: NEJM 2010Blinded M RCTn=1679Primary outcome: 28d mortality15% RRR from 40% mortality2003-2007
De Backer: NEJM 2010Adverse eventsA priori subgroupsSeptic 62.1%Cardiogenic 16.7%Hypovolaemic 15.6%
Blinded MC RCTn=779Primary outcome: 28d mortality10% ARR from 60% mortalityVasopressin (max 0.03 u/min) vsnoradrenaline (5...
Russell: CCM 2009Norepinephrine 131/293 (44.7%)Vasopressin 106/295 (35.9%)P=0.03Norepinephrine 19/89 (21.3%)Vasopressin 34...
Systematic review: 2011Havel: Cochrane Collaboration 2011Additional 17 studies identified: total 23N=3212, 1629 mortality ...
On current high quality evidence:Noradrenaline is the probably vasoactive drug of choice.Adrenaline is equieffective, with...
Non-catecholamine “inodilators”
The SURVIVE StudyMebazza: JAMA 2007Blinded MC RCTn=1320Primary outcome: 180d mortalitySecondary outcome: δBNPLevosimendan ...
ConclusionsAn body of higher-quality, investigator-initiated trials ofcatecholamines on patient-centred outcomes in critic...
InterpretationThe role of catecholamines for the treatment of shock isevolving from “rescue” therapy to “neurohormonalaugm...
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?
John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?
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John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?

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John Myburgh brings his experience and analysis to bear upon the use of catecholamines in the crashing patient. The second talk in the Resuscitation plenary.

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John Myburgh: Catecholamines, Resuscitation and Resurrection: Fact or Fiction?

  1. 1. Catecholamines:resuscitation or resurrection?UNSWJohn MyburghMBBCh PhD FCICM FAICDThe George Institute for Global HealthSt George Clinical School, University of New South Wales
  2. 2. What is knowledge?
  3. 3. Hein: Cell Tissue Research 2006Neurohormonal vasoregulation
  4. 4. Neurohormonal vasoregulationSadowska : J Physiol Pharm 2006VPNoradrenalineAdrenalineCortisol
  5. 5. Mean arterialpressureCardiac outputRight atrialpressureMean systemic pressurePerfusion pressureUnstressedvolumeStressedvolumeVenous returnArteriolar toneHaemodynamics15mmHg15mmHg5mmHg60mmHg60mmHgGuyton 1953
  6. 6. Barcroft: Lancet 1949n=7Human studiesGoldenberg : Arch Int Med 1950
  7. 7. Steele: Curr Opin Crit Care 2000What the textbooks say …….
  8. 8. What is “best” evidence?
  9. 9. Synthetic catecholamines
  10. 10. OHCH2CH2NHCHCH2CH2OHCH3OH .HClCHOHCH2 NHCHOHOHCH3CH3OHCH2CH2NHCH2CH2CH2CH2CH2CH2NHCH2CH2OH.2HClIsoprenalineDobutamineDopexamineCH2CH2NH2OHOHHCOHCH2NHCH3OHOHDopamine Adrenaline
  11. 11. CostDose Cost(AUD)Adrenaline 6 mg 11Noradrenaline 6mg 20Dopamine 400mg 37Dobutamine 500mg 119Dopexamine 50mg 390Isoprenaline 6mg 410Milrinone 8mg 500Levosimendan 12.5mg 1420
  12. 12. Dobutamine and sepsisn Dose(µg/kg/min)Endpoint Mortality GradeHayes 1994 100 5-200 DO2, VO2 34 v 54* IIIYu 1993 67 5-20 DO2, VO2 34 v 44 IIITuschmidt 1992 51 5 + DO2, VO2 59 v 72% IVShoemaker 1986 10 5 – 10 + DO2, VO2 Not stated IVShoemaker 1989 25 2.5-10 DO2, VO2 Not stated IVShoemaker 1991 12 2.5- 10 DO2, VO2 Not stated IVTell 1987 6 2.5-20 SBP, UO 50% IVKrachman 1994 12 5 + DO2, VO2 100% IVLejus 1991 10 5-15 PAOP, MAP 50% IVJardin 1981 19 3.6-28 DO2, VO2 Not stated IVVincent 1990 84 5 DO2, VO2 Not stated IV(11) 396Rudis CCM 1996
  13. 13. Maximising DO2 : the evidenceAchieving “supranormal” DO2 andVO2 does not affect mortalityMay benefit preoperativelyResponders ? index of reserve-0.1-1 1 10 100Shoemaker 1988Tuschmidt 1992Yu 1993Boyd 1993Hayes 1994Yu 1994Gattinoni 1995Combined RelativeRisk 0.86 (0.62 - 1.2)Heyland CCM 1996
  14. 14. Catecholamines and septic shockn Drug Dose Endpoint GradeDuranteau 1999 12 Adr ± Nor MAP >80 pHi IIIJoly 1999 14 Dob 7.5 µg/kg/min pHi, CO IVLevy 1999 24 Dob ± Dpx 5 / 1 µg/kg/min pHi, CO IIIReinelt 1999 6 Phenyleph MAP > 60 PHi IVMartin 1999 26 Dob ± Nor MAP >75 CO, SVR, MAP IIIRhodes 1999 36 Dob 10 µg/kg/min Mortality pred IVCreteur 1999 36 Dob 5 + 10 µg/kg/min pHi, CO IIIBriegel 2000 40 Dob/Nor/Adr Shock resolution Requirement III(8) 194Steele: Curr Opin Crit Care 2000
  15. 15. “Goal Directed Therapy”Rivers: NEJM 2001
  16. 16. Human trialsNo conclusive evidenceDescriptive, observational, underpoweredVariable dose ranges, selection criteriaVariable endpointsVariable mortality“Oxygen delivery” focusCommercial influencePublication biasMisapplication of biological principles
  17. 17. Evidence-based guidelinesDellinger: CCM 2004, 2008
  18. 18. “Inotropes”Dellinger: ICM 2008
  19. 19. Biologically plausible, but unrelated to the evidence presentedPublication biasIntervention biasRegional biasAdrenaline gets a “bad” wrapConcerns about dopamine.“Vasopressors”Dellinger: ICM 2008
  20. 20. Noradrenaline + DobutamineAdrenalinepHiHoursAdrenaline “toxicity”?Splanchnic ischaemiaLevy: ICM 1997n=23Malaria n=13Severe sepsis n=10Changeinlactate(mmol/L)DopamineAdrenalineLactic acidosisDay: Lancet 1996
  21. 21. What is “best” evidence?
  22. 22. Mullner: Cochrane Collaboration 2007
  23. 23. Systematic review: 2007Intervention n RR 95%CIADR v NOR 0 0 0NOR + DOB vs ADR 52 0.98 0.57 to 1.67NOR vs DOP 62 0.88 0.57 to 1.36Mullner: Cochrane Collaboration 2007
  24. 24. What is “best” evidence?
  25. 25. Myburgh: ICM 2008Relative effectiveness blinded MC RCTn=280Primary outcome: Clinician-prescribed target MAP > 24 hours2004-2006All patientsSevere Sepsis
  26. 26. Myburgh: ICM 2008
  27. 27. Annane: Lancet 2007Blinded MC RCTn=330Primary outcome: D28 mortality1999-2004
  28. 28. No difference in secondary outcome measures:Haemodynamic endpointsDose of drug(s)Organ failure resolutionICU LOSEpinephrine associated with lactic acidosisAnnane: Lancet 2007
  29. 29. De Backer: NEJM 2010Blinded M RCTn=1679Primary outcome: 28d mortality15% RRR from 40% mortality2003-2007
  30. 30. De Backer: NEJM 2010Adverse eventsA priori subgroupsSeptic 62.1%Cardiogenic 16.7%Hypovolaemic 15.6%
  31. 31. Blinded MC RCTn=779Primary outcome: 28d mortality10% ARR from 60% mortalityVasopressin (max 0.03 u/min) vsnoradrenaline (5-15µg/min)Russell: NEJM 2008
  32. 32. Russell: CCM 2009Norepinephrine 131/293 (44.7%)Vasopressin 106/295 (35.9%)P=0.03Norepinephrine 19/89 (21.3%)Vasopressin 34/101 (33.7%)P=0.06
  33. 33. Systematic review: 2011Havel: Cochrane Collaboration 2011Additional 17 studies identified: total 23N=3212, 1629 mortality outcomesSensitivity analysis of 10 studies with low risk of bias
  34. 34. On current high quality evidence:Noradrenaline is the probably vasoactive drug of choice.Adrenaline is equieffective, with transient metabolic effectsDopamine associated with adverse effects, particularly arrhythmiaDobutamine has no demonstrable benefitVasopressin may have catecholamine-sparing effects, but noclinical benefit in septic shockHydrocortisone …… unprovenDellinger: ICM 2012
  35. 35. Non-catecholamine “inodilators”
  36. 36. The SURVIVE StudyMebazza: JAMA 2007Blinded MC RCTn=1320Primary outcome: 180d mortalitySecondary outcome: δBNPLevosimendan (12µg/kg + 0.1 µg/kg/min) x 2 h vs dobutamine (5-40 µg/kg/min)
  37. 37. ConclusionsAn body of higher-quality, investigator-initiated trials ofcatecholamines on patient-centred outcomes in critically illpatients is finally emerging.The is no evidence of superiority of any of the currently usedcatecholamines, used solely or in combination, overnoradrenaline or adrenaline on resolution of shock,development or resolution of organ failure or mortality.Catecholamine-sparing strategies with vasopressin andcorticosteroids have an undefined, unproven role.
  38. 38. InterpretationThe role of catecholamines for the treatment of shock isevolving from “rescue” therapy to “neurohormonalaugmentation” therapy in vulnerable patients.It is biologically implausible that synthetic catecholaminecompounds will produce improvements in patient-centredoutcomes.Current evidence-based guidelines and bundles will needrevision to accord with global considerations outside theimperative of industry.

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